Genetic Variant OR6S1:p.Ala329Pro (chr14-20640707-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001001968.1(OR6S1):c.985G>C(p.Ala329Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000257 in 1,362,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

OR6S1
NM_001001968.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0180

Publications

1 publications found

Variant links:

Genes affected

OR6S1 (HGNC:15363): (olfactory receptor family 6 subfamily S member 1) Olfactory receptors interact with odorant molecules in the nose, to initiate a neuronal response that triggers the perception of a smell. The olfactory receptor proteins are members of a large family of G-protein-coupled receptors (GPCR) arising from single coding-exon genes. Olfactory receptors share a 7-transmembrane domain structure with many neurotransmitter and hormone receptors and are responsible for the recognition and G protein-mediated transduction of odorant signals. The olfactory receptor gene family is the largest in the genome. The nomenclature assigned to the olfactory receptor genes and proteins for this organism is independent of other organisms. [provided by RefSeq, Jul 2008]

OR6S1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034802377).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR6S1	NM_001001968.1 link	c.985G>C	p.Ala329Pro	missense_variant	Exon 1 of 1	ENST00000320704.3	NP_001001968.1	Q8NH40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR6S1	ENST00000320704.3 link	c.985G>C	p.Ala329Pro	missense_variant	Exon 1 of 1	6	NM_001001968.1	ENSP00000313110.3		Q8NH40

Frequencies

GnomAD3 genomes

AF:

0.00000701

AC:

AN:

142582

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000404

AC:

AN:

247258

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000279

AC:

AN:

1220380

Hom.:

Cov.:

AF XY:

0.0000230

AC XY:

AN XY:

609850

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27160

American (AMR)

AF:

0.00

AC:

AN:

40088

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20060

East Asian (EAS)

AF:

0.00

AC:

AN:

25218

South Asian (SAS)

AF:

0.00

AC:

AN:

82758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4144

European-Non Finnish (NFE)

AF:

0.0000354

AC:

AN:

931436

Other (OTH)

AF:

0.0000211

AC:

AN:

47422

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000701

AC:

AN:

142582

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

68646

show subpopulations

African (AFR)

AF:

0.0000256

AC:

AN:

38996

American (AMR)

AF:

0.00

AC:

AN:

14072

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3398

East Asian (EAS)

AF:

0.00

AC:

AN:

4392

South Asian (SAS)

AF:

0.00

AC:

AN:

4220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66128

Other (OTH)

AF:

0.00

AC:

AN:

2008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.985G>C (p.A329P) alteration is located in exon 1 (coding exon 1) of the OR6S1 gene. This alteration results from a G to C substitution at nucleotide position 985, causing the alanine (A) at amino acid position 329 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

1.8

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0020

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.24

M_CAP

Benign

0.0020

MetaRNN

Benign

0.035

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.018

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.050

REVEL

Benign

0.018

Sift

Benign

0.14

Sift4G

Uncertain

0.041

Polyphen

0.0

Vest4

0.10

MutPred

0.17

Gain of catalytic residue at L325 (P = 0.0015);

MVP

0.15

MPC

0.015

ClinPred

0.028

GERP RS

-3.8

Varity_R

0.073

gMVP

0.33

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr14-20640707-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over